Thre precise regulation of uterine blood flow during pregnancy is important not only for the survival and growth of the fetus but also for the cardiovascular well-being for the mother. Our preliminary in vitro studied indicted that contractile sensitivity of the uterine artery to norepinephrine, the sympathetic neurotransmitter which plays a key role in moment-to-moment regulation of vascular tone, was decreased in near-term pregnant sheep who had been exposed to long-term high altitude hypoxia. Yet the cellular/molecular mechanisms underlying the vascular adjustments to chronic hypoxia are not understood. Further, the impact of this alteration in vascular contractility on uterine blood flow is unknown. The proposed studies focus on these mechanisms and address the general hypothesis that moderate chronic hypoxia augments pregnancy-induced vascular adjustments of the uterine artery by enhancing endothelial function, and depressing smooth muscle pharmacomechanical coupling. Four of its main corollaries will be addressed by 4 Specific Aims which will test whether moderate chronic hypoxia a) up-regulates endothelial isoform of nitric oxide synthase (ecNOS) activity and gene expression in the uterine artery, b) attenuates pharmacomechanical coupling of alpha1- adrenergic receptors in the uterine artery, c) affects the production of nitric oxide and uterine vascular resistance in vivo in ways similar to in vitro, and test whether d) cGMP plays a key role in chronically hypoxic- induced attenuation of pharmacomechanical coupling in the uterine artery. To acheive these aims, we will measure in vitro uterine artery endothelial nitric oxide release, expression of nitric oxide synthase (ecNOS), smooth muscle alpha/1-adrenergic receptors, inositol 1,4,5-triphosphate (Ip/3) synthesis, IP/3 receptor affinity and density, intracellular free calcium concentration, and calcium sensitivity of contractile myofilaments, and will measure in vivo uterine nitrite/nitrate secretion, uterine blood flow, and vascular resistance in near-term (140 d) pregnant sheep maintained near sea level (approximately 300 m) and at a high altitude ( 3,820 m) from 30 days gestation. The results of the proposed studies will provide important original insights into biochemical. cellular, and physiologic adaptive mechanisms involved in adjusting uteroplacental circulation in response to moderate chronic hypoxia, and will help improve our understanding of maternal cardiovascular disorders and fetal developmental abnormalities associated with the maladaptation of uterine circulation to chronic hypoxia and permit us to address them in a more meaningful way.